Canonical transient receptor potential-6 (TRPC6) channels have been implicated in a variety of chronic kidney diseases including familial and acquired forms of focal and segmental glomerulosclerosis (FSGS) and renal fibrosis following ureteral obstruction. Here we have examined the role of TRPC6 in progression of inflammation and fibrosis in the nephrotoxic serum (NTS) model of crescentic glomerulonephritis. This was assessed in rats with non-functional TRPC6 channels due to genomic disruption of an essential domain in TRPC6 channels (Trpc6 del/del rats) and wild-type littermates (Trpc6 wt/wt rats). Administration of NTS evoked albuminuria and proteinuria observed 4 and 28 days later that was equally severe in Trpc6 wt/wt and Trpc6 del/del rats. By 28 days, there were dense deposits of complement and IgG within glomeruli in both genotypes, accompanied by severe inflammation and fibrosis readily observed by standard histological methods, and also by increases in renal cortical expression of multiple markers (α-smooth muscle actin, vimentin, NLRP3, and CD68). Tubulointerstitial fibrosis appeared equally severe in Trpc6 wt/wt and Trpc6 del/del rats. TRPC6 inactivation did not protect against the substantial declines in renal function (increases in blood urea nitrogen, serum creatinine and kidney:body weight ratio) in NTS-treated animals, and increases in a urine maker of proximal tubule pathology (β2-macroglobulin) were actually more severe in Trpc6 del/del animals. By contrast, glomerular pathology, blindly scored from histology, and from renal cortical expression of podocin suggested a partial but significant protective effect of TRPC6 inactivation within the glomerular compartment, at least during the autologous phase of the NTS model.
Keywords: BUN, blood urea nitrogen; CKD, chronic kidney disease; Chronic kidney disease; FSGS, focal and segmental glomerulosclerosis; GBM, glomerular basement membrane; Glomerulonephritis; IL-1β, interleukin 1β; NLRP3, NOD-like receptor pyrin domain containing-3 protein; NTS, nephrotoxic serum; PAN, puromycin amino nucleoside; PAS, periodic acid-Schiff’s stain; Renal fibrosis; SMA, α-smooth muscle actin; TCA, trichloroacetic acid; TNF, tumor necrosis factor; TRPC3, canonical transient receptor potential-3 channel; TRPC5, canonical transient receptor potential-5 channel; TRPC6; TRPC6, canonical transient receptor potential-6 channel; UUO, unilateral ureteral obstruction; suPAR, soluble urokinase receptor.